C-JUN



Introduction
The c-Jun protein is a member of transcription factors which consist of a basic region leucine zipper region. Originally identified by its homology to v-jun, the oncogene from the avian sarcomoa virus. All these leucine zipper factors bind to DNA in one of two states: homo or heterodimers. In conjunction with the c-Fos protein these two proteins bind to specific regions of DNA strands. Together these two proteins form the c-fos/c-jun complex which help regulate cell growth and differentiation. The members of the jun and fos families include three Jun proteins and four Fos proteins (c-Jun, JunB, JunD,c-Fos, Fos-B, Fra1, and Fra2). Regulation of the complex iteslf is done by interactions between the protein and DNA in addition to the protein-protein interactions between each of the leucine zipper domains.

Structure Overview


The structure of c-Jun is comprised of a leucine zipper as previously stated. This dimerization motif may be in one of two classes, both of which are required for DNA-binding transcription factors; the basic-domain leucine zipper proteins (bZIP) and the basic helix loop-helix-leucine zipper proteins(bHLH-ZIP). The strand becomes an elongated coiled coil. This is formed by residues at the a and d positions in each of the two monomers, whereby they create hydrophobic centers which conform to the "knobs into holes" model by Crick. . Amino acids at these a and d positions are each surrounded by 4 additional residues from adjacent a-helix monomer.

The a and d residues each exhibit varying types of packing in terms of this "knobs into holes" theory. According to Harbury et al.(24) the leucines at the a positions are packed "parallel" in such a way that the C-alpha-C-beta bond vector lies in a parallel manner to the C-alpha-C-alpha vector at the base of the acceptor hole on adjacent helix. Whereas the opposite is true for the leucines in the d positions. Here the residues are packed in a "perpendicular" nature. The bond vector of the C-alpha-C-beta pack approximately perpendicular to the C-alpha-C-alpha vector at the base of the hole of the second helix in which it packs. Therefore only the leucine side chains in the a positions, which point away from the boundary, make van der Waals interactions.

Protein Function
The primary function of c-Jun is in regards to DNA transcription. Specifically, the protein is involved in proliferation, apoptosis, oncogenic transformation and various cellular processes. For instance cells which lack an allele for c-jun have been shown to stunt growth both in vitro and in vivo. Whereas a prolonged and therefore strong induction of c-jun has been in response to such things as tumor necrosis factor or stress inducing stimuli such as ultra violet radiation.

Protein Regulation
Changes made in the phosphorylation state of specific amino acids is one means by which c-Jun regulates transcription. To date two seperate sites of phosphorylation have been identified. One is located at the N-terminal end in which the amino acids Ser63 and Ser73 are phosphorylated in response to ras expression. When ras is expressed, and Ser63 and Ser73 are phosphorylated,and transcriptional activity of c-Jun increases. The second site is located at the C-terminal which is very close in proximity to the DNA binding domain. Here the residues are Thr214, Ser226, and Ser 232. Unlike the two serines at the N-terminal end, phosphorylation at the C-terminal end inhibits DNA binding to c-Jun. Therefore with the expression of such oncogenes as ras dephsphorylation of these three residues occurs.

Psychological Influences
The stress-induced signaling cascade may also active c-Jun by phosphorylation. The N-ternminal protein kinase phosphorylates Ser63 and Ser73. Another mechanism for the activation however is interestingly through intracellular calcium concentrations. Increasing these concentrations by opening the L-type voltage gated calcium channels leads to serines phosphorlation. It was found that the N-terminus contains both calcium and stress-regulated transcriptional activation domains. According to the study,distinct mechanisms of c-Jun control function by calcium and stress signals.

Additional Resources
To See Additional information, see: Transcription and RNA Processing

3D structure of C-JUN
1jun – hCJUN leucine zipper domain – human – NMR

1jnm - hCJUN leucine zipper domain + DNA

1fos – hCJUN + p55 c-Fos + DNA